1. Field of the Invention
This invention relates to a process for the preparation of esters of 5-methylpyrazine-2-carboxylic acid-4-oxide and its conversion to pharmaceutically acceptable organic and inorganic salts thereof.
2. Description of the Related Art
It has been our endeavor to synthesize the pharmacological acceptable salts of the 5-methylpyrazinecarboxylic acid via a novel route that will allow us to manufacture these in high purity.
Hydrogen peroxide combined with tungstic acid is an inexpensive, versatile and relatively stable oxidizing agent that has been widely used for a number of functional group transformations including epoxidation of alkenes, diol formation, oxidative alkene cleavage to form dioic acids, and formation of α-hydroxy ketones. Tungstic acid and hydrogen peroxide are also known to oxidize sulfides to sulfones, and amines to oximes, nitrones, hydroxamic acids, and nitroso compounds.
Sodium tungstate has been used in combination with hydrogen peroxide for the conversion of the 5-methylpyrazinecarboxamide-4-oxide. Hydrogen peroxide in combination with ammonium heptamolybdate is known for epoxide formation and the oxidation of secondary alcohols in preference to primary alcohols.
5-Methylpyrazinecarboxylic acid-4-oxide has been produced by several methods described in the literature. Examplary methods include the following.    1. It is made by the oxidation of the 5-methylpyrazinecarboxylic acid using hydrogen peroxide and a tungstate or molybdate catalysts as described in Japanese Patents No. 62263164 and European Patent No. 201934.    2. It is also prepared by peracid oxidation of the 5-methylpyrazinecarboxamide (from a mixed anhydride) followed by basic hydrolysis of the amide oxide and pH adjustment (U.S. Pat. No. 4,051,245).
We have chosen a more stable intermediate, the corresponding esters in place of the acid and the carboxamide, to bring about this transformation. This allows us to produce the material in very high purity as the pure intermediates can either be used as such or can be further purified.